scholarly journals Nrf2 Is an Attractive Therapeutic Target for Retinal Diseases

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Yasuhiro Nakagami
Keyword(s):  
Oxidative Stress ◽  
Neuronal Degeneration ◽  
Antioxidant Response ◽  
Related Factor ◽  
Retinal Diseases ◽  
Age Related ◽  
Nrf2 Signaling Pathway ◽  
Genes Encoding ◽  
Antioxidant Response Elements ◽  
Nrf2 Activator

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of Nrf2 functions is one of the critical defensive mechanisms against oxidative stress in many species. The retina is constantly exposed to reactive oxygen species, and oxidative stress is a major contributor to age-related macular diseases. Moreover, the resulting inflammation and neuronal degeneration are also related to other retinal diseases. The well-known Nrf2 activators, bardoxolone methyl and its derivatives, have been the subject of a number of clinical trials, including those aimed at treating chronic kidney disease, pulmonary arterial hypertension, and mitochondrial myopathies. Recent studies suggest that Nrf2 activation protects the retina from retinal diseases. In particular, this is supported by the finding that Nrf2 knockout mice display age-related retinal degeneration. Moreover, the concept has been validated by the efficacy of Nrf2 activators in a number of retinal pathological models. We have also recently succeeded in generating a novel Nrf2 activator, RS9, using a biotransformation technique. This review discusses current links between retinal diseases and Nrf2 and the possibility of treating retinal diseases by activating the Nrf2 signaling pathway.

scholarly journals Ishige okamurae Ameliorates Methylglyoxal-Induced Nephrotoxicity via Reducing Oxidative Stress, RAGE Protein Expression, and Modulating MAPK, Nrf2/ARE Signaling Pathway in Mouse Glomerular Mesangial Cells

Foods ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2000
Author(s):  
Mingyeong Kim ◽  
Chiheung Cho ◽  
Changjun Lee ◽  
Bomi Ryu ◽  
Sera Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mesangial Cells ◽  
Apoptotic Cell ◽  
Antioxidant Response ◽  
Diabetic Complication ◽  
Related Factor ◽  
Glomerular Mesangial Cells ◽  
Ishige Okamurae ◽  
Age Related

Advanced glycation end-products (AGEs) such as methylglyoxal (MGO) play a vital role in the pathogenesis of nephropathy, a diabetic complication. In the present study, we evaluated the anti-glycation and renal protective properties of Ishige okamurae extract (IOE) against AGE-induced oxidative stress. HPLC analysis confirmed that bioactive phlorotannins such as diphlorethohydroxycarmalol and ishophloroglucin A are predominantly present in IOE. IOE showed strong anti-glycation activities via inhibition of AGE formation, inhibition of AGE–protein cross-linking, and breaking of AGE–protein cross-links. In addition, in vitro studies using mesangial cells demonstrated that IOE effectively suppressed intracellular reactive oxygen species production, intracellular MGO accumulation, and apoptotic cell death by MGO-induced oxidative stress, in addition to regulating the expression of proteins involved in the receptor for AGEs and nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements (ARE) signaling pathways. Therefore, IOE can serve as a natural therapeutic agent for the management of AGE-related nephropathy.

scholarly journals Anti-Viral Potential and Modulation of Nrf2 by Curcumin: Pharmacological Implications

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1228
Author(s):  
Mahdie Rahban ◽  
Mehran Habibi-Rezaei ◽  
Mansoureh Mazaheri ◽  
Luciano Saso ◽  
Ali A. Moosavi-Movahedi
Keyword(s):  
Oxidative Stress ◽  
Viral Infections ◽  
Biological Effects ◽  
Curcuma Longa ◽  
Redox Balance ◽  
Antioxidant Response ◽  
Potential Effect ◽  
Related Factor ◽  
Balance State ◽  
Nrf2 Activator

Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential transcription factor that maintains the cell’s redox balance state and reduces inflammation in different adverse stresses. Under the oxidative stress, Nrf2 is separated from Kelch-like ECH-associated protein 1 (Keap1), which is a key sensor of oxidative stress, translocated to the nucleus, interacts with the antioxidant response element (ARE) in the target gene, and then activates the transcriptional pathway to ameliorate the cellular redox condition. Curcumin is a yellow polyphenolic curcuminoid from Curcuma longa (turmeric) that has revealed a broad spectrum of bioactivities, including antioxidant, anti-inflammatory, anti-tumor, and anti-viral activities. Curcumin significantly increases the nuclear expression levels and promotes the biological effects of Nrf2 via the interaction with Cys151 in Keap1, which makes it a marvelous therapeutic candidate against a broad range of oxidative stress-related diseases, including type 2 diabetes (T2D), neurodegenerative diseases (NDs), cardiovascular diseases (CVDs), cancers, viral infections, and more recently SARS-CoV-2. Currently, the multifactorial property of the diseases and lack of adequate medical treatment, especially in viral diseases, result in developing new strategies to finding potential drugs. Curcumin potentially opens up new views as possible Nrf2 activator. However, its low bioavailability that is due to low solubility and low stability in the physiological conditions is a significant challenge in the field of its efficient and effective utilization in medicinal purposes. In this review, we summarized recent studies on the potential effect of curcumin to activate Nrf2 as the design of potential drugs for a viral infection like SARS-Cov2 and acute and chronic inflammation diseases in order to improve the cells’ protection.

scholarly journals Antioxidants Enhance Mammalian Proteasome Expression through the Keap1-Nrf2 Signaling Pathway

2003 ◽  
Vol 23 (23) ◽  
pp. 8786-8794 ◽  
Author(s):  
Mi-Kyoung Kwak ◽  
Nobunao Wakabayashi ◽  
Jennifer L. Greenlaw ◽  
Masayuki Yamamoto ◽  
Thomas W. Kensler
Keyword(s):  
Antioxidant Response ◽  
Proteasome Activity ◽  
26S Proteasome ◽  
Proximal Promoter ◽  
Protective Effects ◽  
Protein Levels ◽  
Age Related ◽  
Nrf2 Signaling Pathway ◽  
Antioxidant Response Elements ◽  
Indirect Action

ABSTRACT Proteasomes degrade damaged proteins formed during oxidative stress, thereby promoting cell survival. Neurodegenerative and other age-related disorders are associated with reduced proteasome activity. We show herein that expression of most subunits of 20S and 19S proteasomes, which collectively assemble the 26S proteasome, was enhanced up to threefold in livers of mice following treatment with dithiolethiones, which act as indirect antioxidants. Subunit protein levels and proteasome activity were coordinately increased. No induction was seen in mice where the transcription factor Nrf2 was disrupted. Promoter activity of the PSMB5 subunit of the 20S proteasome increased with either Nrf2 overexpression or treatment with antioxidants in mouse embryonic fibroblasts. Tandem antioxidant response elements in the proximal promoter of PSMB5 that controlled these responses were identified. We propose that induction of the 26S proteasome through the Nrf2 pathway represents an important indirect action of these antioxidants that can contribute to their protective effects against chronic diseases.

scholarly journals A Combination of Herbal Compound (SPTC) Along with Exercise or Metformin more Efficiently Alleviated Diabetic Complications Through Down-Regulation of Stress Oxidative Pathway upon Activating Nrf2-Keap1 axis in AGEs Rich Diet-Induced type 2 Diabetic Mice

2020 ◽  
Author(s):  
Golbarg Rahimi ◽  
Salime Heydari ◽  
Bahare Rahimi ◽  
Navid Abedpoor ◽  
Iman Nicktab ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Exercise Training ◽  
Diabetic Complications ◽  
Combined Treatment ◽  
Antioxidant Response ◽  
Salvia Officinalis ◽  
Calorie Intake ◽  
Related Factor ◽  
Diabetic Mice ◽  
Nrf2 Signaling Pathway

Abstract Background: SPTC is a mix of four herbal components (Salvia officinalis, Panax ginseng, Trigonella foenum-graeceum, and Cinnamomum zeylanicum) which may prevent the development of AGEs rich diet-induced diabetic complication and liver injury via activating the nuclear factor erythroid-2-related-factor-2 (Nrf2) pathway. Nrf2, as a master regulator of antioxidant response elements by activating cytoprotective genes expression, decreases oxidative stress associated with hyperglycemia and increases insulin sensitivity. We hypothesized that the combined effect of SPTC along with exercise could efficiently moderate oxidative stress with more favorable effects in the treatment of diabetes.Methods: We induced diabetes in C57BL/6 mice by AGEs using a diet supplementation and limitation of physical activity. After 16 weeks of intervention, AGEs fed mice were compared to control mice. Diabetic mice were assigned into seven experimental groups (n=5): diabetic mice, diabetic mice treated with SPTC (130 mg/kg), diabetic mice treated with Salvia Officinalis (60 mg/kg), diabetic mice treated with metformin (300 mg/kg), diabetic mice with endurance exercise training, diabetic mice treated with SPTC+metformin (the same as mentioned), diabetic mice treated with SPTC+exercise trainingResults: SPTC+exercise and SPTC+metformin reduced diabetic complications like gain weight, water, and calorie intake, blood glucose, insulin, and GLUT4 content more efficiently than each treatmen. These combinations improved oxidative stress hemostasis by activating the Nrf2 signaling pathway and attenuating keap1 protein more significantly.Conclusions: Eventually, combined treatment of SPTC with exercise and metformin as a novel approach had more beneficial effects to prevent the development of diabetes and oxidative stress associated with hyperglycemia.

scholarly journals Therapeutic Potential of Salviae Miltiorrhizae Radix et Rhizoma against Human Diseases Based on Activation of Nrf2-Mediated Antioxidant Defense System: Bioactive Constituents and Mechanism of Action

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Guo-Hui Li ◽  
Yan-Ru Li ◽  
Ping Jiao ◽  
Yu Zhao ◽  
Hui-Xin Hu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Therapeutic Potential ◽  
Antioxidant Defense System ◽  
Antioxidant Response ◽  
Human Diseases ◽  
Related Factor ◽  
Bioactive Constituents ◽  
Salviae Miltiorrhizae ◽  
Nrf2 Signaling Pathway ◽  
Salviae Miltiorrhizae Radix

Oxidative stress plays a central role in the pathogenesis of many human diseases. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor regulating the intracellular antioxidant response and is an emerging target for the prevention and therapy of oxidative stress-related diseases. Salviae Miltiorrhizae Radix et Rhizoma (SMRR) is a traditional Chinese medicine (TCM) and is commonly used for the therapy of cardiac cerebral diseases. Cumulative evidences indicated that the extract of SMRR and its constituents, represented by lipophilic diterpenoid quinones and hydrophilic phenolic acids, were capable of activating Nrf2 and inhibiting oxidative stress. These bioactive constituents demonstrated a therapeutic potential against human diseases, exemplified by cardiovascular diseases, neurodegenerative diseases, diabetes, nephropathy, and inflammation, based on the induction of Nrf2-mediated antioxidant response and the inhibition of oxidative stress. In the present review, we introduced the SMRR and Nrf2 signaling pathway, summarized the constituents with an Nrf2-inducing effect isolated from SMRR, and discussed the molecular mechanism and pharmacological functions of the SMRR extract and its constituents.

scholarly journals A Nature-Inspired Nrf2 Activator Protects Retinal Explants from Oxidative Stress and Neurodegeneration

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1296
Author(s):  
Maria Grazia Rossino ◽  
Rosario Amato ◽  
Marialaura Amadio ◽  
Michela Rosini ◽  
Filippo Basagni ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nuclear Translocation ◽  
Apoptotic Cell ◽  
Antioxidant Properties ◽  
Antioxidant Response ◽  
Structural Features ◽  
Related Factor ◽  
Retinal Diseases ◽  
Protein Levels ◽  
Retinal Explants

Oxidative stress (OS) plays a key role in retinal dysfunctions and acts as a major trigger of inflammatory and neurodegenerative processes in several retinal diseases. To prevent OS-induced retinal damage, approaches based on the use of natural compounds are actively investigated. Recently, structural features from curcumin and diallyl sulfide have been combined in a nature-inspired hybrid (NIH1), which has been described to activate transcription nuclear factor erythroid-2-related factor-2 (Nrf2), the master regulator of the antioxidant response, in different cell lines. We tested the antioxidant properties of NIH1 in mouse retinal explants. NIH1 increased Nrf2 nuclear translocation, Nrf2 expression, and both antioxidant enzyme expression and protein levels after 24 h or six days of incubation. Possible toxic effects of NIH1 were excluded since it did not alter the expression of apoptotic or gliotic markers. In OS-treated retinal explants, NIH1 strengthened the antioxidant response inducing a massive and persistent expression of antioxidant enzymes up to six days of incubation. These effects resulted in prevention of the accumulation of reactive oxygen species, of apoptotic cell death, and of gliotic reactivity. Together, these data indicate that a strategy based on NIH1 to counteract OS could be effective for the treatment of retinal diseases.

scholarly journals Naturally Occurring Nrf2 Activators: Potential in Treatment of Liver Injury

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Ravirajsinh N. Jadeja ◽  
Kapil K. Upadhyay ◽  
Ranjitsinh V. Devkar ◽  
Sandeep Khurana
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Antioxidant Response ◽  
Chronic Liver ◽  
Related Factor ◽  
Chronic Liver Injury ◽  
Potential Therapeutic Target ◽  
Naturally Occurring ◽  
Liver Injuries ◽  
Nrf2 Signaling Pathway

Oxidative stress plays a major role in acute and chronic liver injury. In hepatocytes, oxidative stress frequently triggers antioxidant response by activating nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor, which upregulates various cytoprotective genes. Thus, Nrf2 is considered a potential therapeutic target to halt liver injury. Several studies indicate that activation of Nrf2 signaling pathway ameliorates liver injury. The hepatoprotective potential of naturally occurring compounds has been investigated in various models of liver injuries. In this review, we comprehensively appraise various phytochemicals that have been assessed for their potential to halt acute and chronic liver injury by enhancing the activation of Nrf2 and have the potential for use in humans.

scholarly journals A Review on Oxidative Stress, Diabetic Complications, and the Roles of Honey Polyphenols

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Visweswara Rao Pasupuleti ◽  
Chandra Sekhar Arigela ◽  
Siew Hua Gan ◽  
Sirajudeen Kuttulebbai Nainamohamed Salam ◽  
Kumara Thevan Krishnan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Antioxidant Response ◽  
Dietary Factors ◽  
The Body ◽  
Related Factor ◽  
Antidiabetic Agent ◽  
Antioxidant Response Elements

Despite the availability of various antidiabetic drugs, diabetes mellitus (DM) remains one of the world’s most prevalent chronic diseases and is a global burden. Hyperglycaemia, a characteristic of type 2 diabetes mellitus (T2DM), substantially leads to the generation of reactive oxygen species (ROS), triggering oxidative stress as well as numerous cellular and molecular modifications such as mitochondrial dysfunction affecting normal physiological functions in the body. In mitochondrial-mediated processes, oxidative pathways play an important role, although the responsible molecular mechanisms remain unclear. The impaired mitochondrial function is evidenced by insulin insensitivity in various cell types. In addition, the roles of master antioxidant pathway nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)/antioxidant response elements (ARE) are being deciphered to explain various molecular pathways involved in diabetes. Dietary factors are known to influence diabetes, and many natural dietary factors have been studied to improve diabetes. Honey is primarily rich in carbohydrates and is also abundant in flavonoids and phenolic acids; thus, it is a promising therapeutic antioxidant for various disorders. Various research has indicated that honey has strong wound-healing properties and has antibacterial, anti-inflammatory, antifungal, and antiviral effects; thus, it is a promising antidiabetic agent. The potential antidiabetic mechanisms of honey were proposed based on its major constituents. This review focuses on the various prospects of using honey as an antidiabetic agent and the potential insights.

scholarly journals Nrf2 Activation Attenuates Acrylamide-Induced Neuropathy in Mice

2021 ◽  
Vol 22 (11) ◽  
pp. 5995
Author(s):  
Chand Basha Davuljigari ◽  
Frederick Adams Ekuban ◽  
Cai Zong ◽  
Alzahraa A. M. Fergany ◽  
Kota Morikawa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathway ◽  
Messenger Rna ◽  
Hepatic Necrosis ◽  
Related Factor ◽  
Necrosis Factor Alpha ◽  
Adult Mice ◽  
Nrf2 Signaling Pathway ◽  
Antioxidant Proteins ◽  
Oxide Synthase

Acrylamide is a well characterized neurotoxicant known to cause neuropathy and encephalopathy in humans and experimental animals. To investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in acrylamide-induced neuropathy, male C57Bl/6JJcl adult mice were exposed to acrylamide at 0, 200 or 300 ppm in drinking water and co-administered with subcutaneous injections of sulforaphane, a known activator of the Nrf2 signaling pathway at 0 or 25 mg/kg body weight daily for 4 weeks. Assessments for neurotoxicity, hepatotoxicity, oxidative stress as well as messenger RNA-expression analysis for Nrf2-antioxidant and pro-inflammatory cytokine genes were conducted. Relative to mice exposed only to acrylamide, co-administration of sulforaphane protected against acrylamide-induced neurotoxic effects such as increase in landing foot spread or decrease in density of noradrenergic axons as well as hepatic necrosis and hemorrhage. Moreover, co-administration of sulforaphane enhanced acrylamide-induced mRNA upregulation of Nrf2 and its downstream antioxidant proteins and suppressed acrylamide-induced mRNA upregulation of tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS) in the cerebral cortex. The results demonstrate that activation of the Nrf2 signaling pathway by co-treatment of sulforaphane provides protection against acrylamide-induced neurotoxicity through suppression of oxidative stress and inflammation. Nrf2 remains an important target for the strategic prevention of acrylamide-induced neurotoxicity.

scholarly journals Crosstalk between Long-Term Sublethal Oxidative Stress and Detrimental Inflammation as Potential Drivers for Age-Related Retinal Degeneration

Antioxidants ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 25
Author(s):  
Lara Macchioni ◽  
Davide Chiasserini ◽  
Letizia Mezzasoma ◽  
Magdalena Davidescu ◽  
Pier Luigi Orvietani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Age Related Macular Degeneration ◽  
Inflammasome Activation ◽  
Related Factor ◽  
Nuclear Factor ◽  
Rpe Cells ◽  
Age Related ◽  
Oxidative Insult

Age-related retinal degenerations, including age-related macular degeneration (AMD), are caused by the loss of retinal pigmented epithelial (RPE) cells and photoreceptors. The pathogenesis of AMD, deeply linked to the aging process, also involves oxidative stress and inflammatory responses. However, the molecular mechanisms contributing to the shift from healthy aging to AMD are still poorly understood. Since RPE cells in the retina are chronically exposed to a pro-oxidant microenvironment throughout life, we simulated in vivo conditions by growing ARPE-19 cells in the presence of 10 μM H2O2 for several passages. This long-term oxidative insult induced senescence in ARPE-19 cells without affecting cell proliferation. Global proteomic analysis revealed a dysregulated expression in proteins involved in antioxidant response, mitochondrial homeostasis, and extracellular matrix organization. The analyses of mitochondrial functionality showed increased mitochondrial biogenesis and ATP generation and improved response to oxidative stress. The latter, however, was linked to nuclear factor-κB (NF-κB) rather than nuclear factor erythroid 2–related factor 2 (Nrf2) activation. NF-κB hyperactivation also resulted in increased pro-inflammatory cytokines expression and inflammasome activation. Moreover, in response to additional pro-inflammatory insults, senescent ARPE-19 cells underwent an exaggerated inflammatory reaction. Our results indicate senescence as an important link between chronic oxidative insult and detrimental chronic inflammation, with possible future repercussions for therapeutic interventions.

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